PowerPoint Presentation:

Drugs derived from structure-based approaches Nelfinavir in the active site of HIV-1 protease: Agouron's AIDS drug nelfinavir (brand name Viracept) is one of the drugs on the market that can be traced directly to structure-based methods.

PowerPoint Presentation:

PowerPoint Presentation:

A. Binding site comprising three binding pockets B. Crystallographic screening locates molecular fragments that bind to one, two or all three pockets C. A lead compound is designed by organizing all three fragments around a core template D. Growing out of a single fragment

Lipinski Rule of Five (1997):

Lipinski Rule of Five (1997) Poor absorption and permeation are more likely to occur when there are more than 5 hydrogen-bond donors, more than 10 hydrogen-bond acceptors, the molecular mass is greater than 500, or the log P value is greater than 5. Further research studied a broader range of physicochemical and structural properties Related problems: Compound toxicity Compound mutagenicity Blood-brain barrier penetration Central nervous system activity

In Silico ADME Models:

In Silico ADME Models Computational methods can predict compound properties important to ADME, e.g. LogP, a liphophilicity measure Solubility Permeability Cytochrome p450 metabolism Means estimates can be made for millions of compouds, helping reduce “attrition” – the failure rate of compounds in late stage

PowerPoint Presentation:

Structure of Cytochrome P450: responsible for primary metabolism of majority of drugs in human body -likely to herald a new era of structure-based design in the modulation of metabolic properties of drugs. Can metabolism properties be modulated?